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Incretin hormones (glucagon-like peptide 1 [GLP-1] and gastric inhibitory peptide) play a key role in glucose homeostasis.
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Two classes of incretin-based therapies are currently available: GLP-1 receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors.
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Potential key benefits of GLP-1 receptor agonist therapy include a low risk of hypoglycemia and a potential for weight loss with treatment.
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GLP-1 receptor agonists have variable effects on glycemia, with short-acting agents having a greater
Incretin-Based Therapies
Section snippets
Key points
Pharmacologic treatment options: incretin-based therapies
As mentioned previously, the incretin effect plays a major role in glucose homeostasis. Although native GLP-1 has been targeted as a therapeutic agent because of its favorable effects on glycemia, its clinical utility in the ambulatory care setting is hindered owing to its extremely short half-life.11 Both native GLP-1 and GIP are quickly cleared following release caused by renal clearance and rapid metabolism by the enzyme dipeptidyl peptidase-4 (DPP-4).23 Owing to the short half-life of
Cardiovascular safety
Given concerns of cardiovascular (CV) safety of drugs for the treatment of DM in recent years,86, 87, 88 the Endocrinologic and Metabolic Drugs Advisory Committee of the FDA redefined the approval criteria for all new medications for the treatment of DM, requiring sponsors to demonstrate that products do not convey an unacceptable CV risk.89 The potential effect of GLP-1 on CV function is an additional area of growing interest, with evidence suggesting that GLP-1 receptors are widely expressed
Summary
Incretin-based therapies are steadily gaining clinical popularity, with many more products in the developmental pipeline. Current treatment recommendations incorporate GLP-1 RAs and DPP-4 inhibitors as important agents for consideration in the treatment of T2DM owing to their low hypoglycemia risk, ability to address postprandial hyperglycemia (DPP-4 inhibitors and short-acting GLP-1 RAs), and potential for weight reduction (GLP-1 RAs).94, 95 These properties may likewise prove advantageous in
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2020, Drug Discovery TodayCitation Excerpt :Currently, two forms of GLP-1-based drugs are clinically available, GLP-1 receptor agonists (GLP-1RAs) and DPP-4 inhibitors, which have shown good control of postprandial blood glucose and in relieving related complications. However, most GLP-1RAs are peptide analogs that have inherent drawbacks, such as high cost, administration by injection, and gastrointestinal adverse events [5]. More importantly, recent studies have found that the use of GLP-1RAs has a potential risk of pancreatitis, heart rate, neoplasms, and C cell hyperplasia [5–7].
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2017, Diabetes and Metabolic Syndrome: Clinical Research and ReviewsCitation Excerpt :In addition to their incretin effect, they exert a glucose-lowering effect with no or only a minimal risk of hypoglycaemia [92,96]. Moreover, DPP-4 inhibitors are weight-neutral, whereas GLP-1 receptor agonists reduce body weight [92]. Several novel medications that target specific molecules and biochemical pathways implicated in the pathogenesis of insulin resistance including glucocorticoid receptor inhibitors and factors that reverse endoplasmic reticulum stress and restore it, promise more effective treatment of insulin resistance in the future.
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Disclosure Statement: J.J. Neumiller receives institutional research grant support from Amylin, AstraZeneca, Johnson & Johnson, Merck, and Novo Nordisk. J.J. Neumiller serves as a consultant to Janssen Pharmaceuticals and Sanofi and serves on the speaker’s bureau for Janssen Pharmaceuticals. No financial support was received for writing this article.